MiRNA genes constitute new targets for microsatellite instability in colorectal cancer

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• Mismatch repair-deficient colorectal cancers (CRC) exhibit widespread microsatellite instability (MSI).
• While MSI commonly impacts coding genes, its effect on non-coding microRNAs (miRNAs) in CRC is largely unknown.
• Human miRNA genes with repeat sequences are rare.

Purpose of the Study:

• To investigate the mutational status of microRNA genes containing repeat sequences in MSI colorectal cancers.
• To identify specific microRNA genes that are frequently mutated in this context.
• To explore the potential functional implications of these mutations in MSI CRC tumorigenesis.

Main Methods:

• Bioinformatic identification of human microRNA genes with mono- or di-nucleotide repeats using miRbase V15.
• Mutational analysis of selected microRNA genes in a large series of MSI CRC cell lines and primary tumors.
• Statistical analysis using a maximum likelihood method to assess mutation frequencies and selective pressures.
• Sequencing and quantitative PCR to evaluate miR-1303 expression levels in relation to its mutational status.

Main Results:

• Out of 27 identified microRNA genes with repeats, 15 showed instability in MSI CRC.
• MicroRNA genes were categorized into two groups based on mutation frequency.
• Three microRNA genes (hsa-mir-1273c, hsa-mir-1303, hsa-mir-567) exhibited frequent (≥80%) mutations, sometimes bi-allelic, in MSI tumors.
• No direct correlation was found between miR-1303 mutations and its mature expression levels in MSI cell lines.

Conclusions:

• Human miRNA genes with DNA repeats are generally rare and relatively protected from MSI-driven mutations in MMR-deficient CRC.
• Specific miRNAs, notably miR-1303, are frequently mutated in MSI CRC, warranting further investigation.
• Functional studies are needed to determine if mutated miRNAs, particularly miR-1303, contribute to MSI tumorigenesis.